Lower urinary tract diseases are the state where disorder exists in any of the bladder and excretory path thereof, which is recognized and diagnosed as lower urinary tract symptoms. The lower urinary tract symptoms are classified into urination symptom, post-urination symptom, pooled urine symptom, pain in reproductive organs and/or lower urinary tract, etc. Urination symptom is appeared during an urination phase and is a symptom such as reduced urinary stream, divided urinary stream, stopped urinary stream, retarded urination, urination by abdominal pressure and terminal dropping. Post-urination symptom is a symptom which is appeared immediately after urination such as sensation of residual urine and urine dropping after urination. Pooled urine symptom is appeared during a pooled urine phase and is a symptom such as pollakiuria during daytime, pollakiuria during the night, urgency of urination, urinary incontinence and exaltation or lowering of bladder sense. Examples of pain in reproductive organs and/or lower urinary tract are bladder pain, urinary tract pain, vulvar pain, vaginal pain, scrotal pain, perineal pain, pelvic pain.
Causes for lower urinary symptoms include (1) disorder of nerve governing the bladder and/or the urethral sphincter caused by spinal damage, cerebrospinal tumor, cerebrospinal blood vessel disorder, myelitis, multiple sclerosis, Parkinson's disease, myelomeningocele, radical operation for uterine cancer, radical operation for rectal cancer, etc.; (2) stimulation to bladder mucosa, inflammation or fibrosis of bladder muscle layer by lesion of bladder wall such as cystitis, prostatitis, calculus at the lower end of the urinary tract and bladder cancer; (3) injury of urethral sphincter; and (4) presence of obstructive lesion of the urinary tract by prostatic hyperplasia, prostatic cancer, bladder neck sclerosis, urethral stricture, etc. In the treatment therefor, treatment of causing diseases therefor is fundamental. When the treatment cannot be carried out, symptomatic treatment is carried out.
Among the lower urinary tract diseases, cystitis means infectious or non-infectious inflammation mostly in bladder mucosa and tissues under the mucosa. Sometimes, it is extended to muscular coat. By its clinical course, it is usually classified into acute cystitis and chronic cystitis. By the presence or absence of obstructive diseases of lower the urinary tract, it is classified into simple cystitis and complexity cystitis. Generally, there are many cases where simple cystitis proceeds acutely and well reacts to antibacterial agents while complexity cystitis proceeds chronically and hardly reacts to antibacterial agents whereby it is sometimes called intractable cystitis. When the cause cannot be identified in intractable cystitis, the cystitis is called primary interstitial cystitis while interstitial cystitis, bacterial intractable cystitis, hemorrhagic cystitis, eosinophilic cystitis, etc. which is caused by the following (1) to (5) are called secondary interstitial cystitis. Thus, (1) infectious diseases of the bladder, the urethra, the prostate gland and the vagina; (2) cystitis by tuberculosis or bacillus Calmette-Guerin (hereinafter, it may be referred to as BCG); (3) drug-induced cystitis by, such as, cyclophosphamide; (4) radiation cystitis; and (5) cancer of the bladder, the uterus, the vagina and the urethra (refer to Iyaku Journal, volume 31, no. 3, page 81, published in 1995; Hainyo Shogai Practice, volume 12, no. 1, page 36, published in 2004).
With regard to the bacterial intractable cystitis, bladder tuberculosis is a representative one. Bladder tuberculosis shows strong cystitis syndrome and pyuria. Common antibacterial agents are ineffective therefor. Hemorrhagic cystitis is cystitis where strong hematuria is a chief complaint. There are various causes therefor and it is not a single disease. Main causes are (1) virus such as adenovirus and influenza virus; (2) bacteria such as Escherichia coli, proteus and Pseudomonas aeruginosa and other microorganisms; and (3) physical and/or chemical stimulation(s) such as irradiation of radioactive ray and administration of agents (e.g., cyclophosphamide, hexamine mandelate and methicillin). There were some cases which were believed to be allergic. However, usually, it is not easy to prove to be surely allergic. Additionally, frequency thereof is not clear as well. Although eosinophilic cystitis shows the same symptom and pyuria as in the case of acute bacterial cystitis, urine culture is negative and antibacterial agents are ineffective. Its pathology is an allergic reaction to agents having an anti-allergic activity. Although tranilast is representative, other anti-allergic agents may also cause the same cystitis. From a pathological view, chief ones are chronic inflammation observations without characteristics. Although there are many cases which are easily recovered by ceasing the administration of the causing agents, it is sometimes necessary to administer steroid or, further, extract the bladder if recovery is hardly achieved.
Primary interstitial cystitis is positioned as a chronic inflammatory disease of bladder interstitial tissue where cause is ambiguous without urinary infection or specific pathological observation in which chief symptoms are urine accumulation symptom such as strong pollakiuria (e.g., there are some cases where about 6 to 70 urinations a day are necessary) and urinary urgency, and pain and unpleasant sensation of generative organs and/or lower the urinary tract in urine accumulation, urination and post-urination. In 1987, although NIH (National Institute of Health) of the United States issued diagnostic criteria for the studies of primary interstitial cystitis, they have been said to be still insufficient. Additionally, in the United States, although it has been said that there are as many as about 700,000 patients and 90% thereof are female, little is known about this diseases. It has been said that the causes for this disease include such as lymphatic disorder, chronic infectious disease, neural disorder, mental disorder, autoimmune disease, vasculitis, toxic factor in urine and destruction of defensive function of the bladder and mast cell. However, the real causes have not been made clear yet (Rinsho Hinyokika, volume 52, no. 9, page 635, published in 1998). Among them, injury of glycosaminoglycan (hereinafter, abbreviated as GAG) is believed to be an important factor. Permeation of bladder mucosa is enhanced by deficiency of GAG, and not only potassium but also normal substances in urine are permeated through the mucosa to stimulate C-fiber in sensory nerve and activate mast cells. It has been believed that such a cascade is induced one after another to occur the symptom. At present, a method for treating this primary interstitial cystitis includes the method which is not for complete recovery but a mere symptomatic treatment. Methods such as a hydraulic expansion method where the bladder which is fibrosed and contracted is mechanically expanded and an intravesical injection therapy of heparin preparation, dimethyl sulfoxide preparation, hyaluronic acid preparation, resiniferatoxin preparation, botulinum toxin preparation, etc. with expectations such as mucosa repair, anti-inflammatory activity, anti-allergic activity and suppression of activation of C-fiber are carried out. In the case of internal agent, improvement in symptom by a cholinolytic agent which is an agent for pollakiuria which suppresses the movement of bladder smooth muscle is exceptional. Although administration of pentosan polysulfate sodium (Elmiron [registered trade mark]) which is a heparin analog with expectations of repairing and anti-inflammatory activities, and administration of antidepressant, analgesic/anti-inflammatory agent, antispasmodic agent, anti-histaminic agent and anti-allergic agent with expectations such as analgesic activity, anti-inflammatory activity and anti-allergic activity have been carried out, no useful treating agent has been found yet.
Prostaglandin (PG) E2 has been known as a metabolite in the arachidonate cascade. It has been known that PGE2 possesses cyto-protective activity, uterine contractive activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity and so on.
A recent study has proved existence of various PGE2 subtype receptors possessing a different physiological or pharmacological role from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3, and EP4 (Negishi M., et al., J. Lipid Mediators Cell Signaling; 12, 379-391 (1995)).
With regard to the finding for PG and urination symptom, topical intravesical therapy by PGE1 or PGE2 was tried for hemorrhagic cystitis by administration of cyclophosphamide which is an anti-cancer agent. Although prevention of getting serious of cystitis, hemostatic effect and the like were demonstrated, it is known the fact that symptom of bladder irritation was induced at the same time (Rinsho Ketsueki, volume 36, no. 8, page 728, published in 1995), that intravesical injection of PGE2 and EP1 and EP3 agonists to healthy persons induce symptom of bladder irritation (Urological Research, volume 18, no. 5, page 349, published in 1990) and that an intravesical injection therapy of PGE2 with an object of promotion of urination to patients suffering from urinary retention is effective (European Urology, volume 4, no. 5, page 366, published in 1978). They show that compounds which acts on PGE2 receptors have promotion of urination function (worsening of urine accumulation symptom) and recovery from cystitis (reduction of urine accumulation symptom), which are contrary each other.
Among PGE2 receptors, it is known that compounds which have antagonistic activity to EP1 are useful as preventive and/or treatment agents for pollakiuria (refer to WO 03/43655) and are useful as preventive and/or treatment agents for urinary incontinence (refer to WO 02/15902).
However, it isn't reported that EP4 agonist relates to lower urinary tract diseases.